tbuckley/cabot-search huggingface dataset:
The prognostic ability of immune scoring system Immunoscore in patients with localized colon cancer: A systematic review and meta-analysis.
Authors: John Lois Padayao, Carlos Dy
Journal: Journal of Clinical Oncology (2023)

2565 Background: Assessment of tumor recurrence risk as well as prognosis in resectable colon cancer are still mainly based on the histopathological criteria of tumor invasion reflected in the TNM classification. Robust data in colorectal tumor research show the value of tumor microenvironment and tumor‐infiltrating lymphocytes (TILs) as novel parameters to predict recurrence and survival. The utility of the derived tumor Immunoscore via digital pathology is now being promoted to refine the prognosis of early colon cancer patients together with the TNM staging to guide treatment decisions, but is not yet a recommendation in international consensus guidelines. This study assessed the prognostic value of this diagnostic tool in predicting clinical outcomes. Methods: A systematic literature search using PubMed, Embase, and Cochrane CENTRAL Library was conducted to identify observational or randomized controlled studies from January 2008 and December 2022 according to pre- specified inclusion and exclusion criteria which examined the relationship between Immunoscore and long-term prognosis (overall survival and disease free survival) in patients with localized colon cancer. Hazard ratios with 95% confidence interval for overall survival (OS) and disease-free survival (DFS) were extracted. Pooled estimates of the prognostic ability of Immunoscore were obtained using bi-variate random effects model. Statistical heterogeneity between studies was evaluated with I 2 statistics and explored through sensitivity analysis. Results: A total of 5,718 patients from 11 studies were included in the meta-analysis. Moderate heterogeneity between studies for both DFS (I 2 = 27%) and OS (I 2 = 33%) was seen. The pooled analysis indicated that compared to those with high Immunoscore, colon cancer patients with low Immunoscore were associated with shorter disease-free survival (HR 1.75, 95% CI 1.53 - 2.49) and overall survival (HR 1.87 95% CI 1.45 – 2.13). In the subgroup analyses, this association was consistent across geographic regions and maximum time of follow up. Conclusions: A low Immunoscore was significantly associated with poorer clinical outcomes in terms of disease-free survival and overall survival. The use of Immunoscore provides valuable estimate of the risk of recurrence in patients with early colon cancer and has the potential to greatly affect treatment decisions in conjunction with the existing risk assessment system.
Importance of patient related outcomes in diagnosing fatigue related to immunotherapy treatment in patients with lung cancer: A real life study.
Authors: Maria-Teresa Almodovar, Mariana Picado, Carina Gaspar
Journal: Journal of Clinical Oncology (2023)

e14709 Background: Lung cancer is a common cancer with a dismal prognosis that was improved with treatment with check-point inhibitors (CPI). Fatigue is the most frequent adverse event of CPI, often undervalued by physicians. Patient report outcomes may be a key to overcome underdiagnose of fatigue. Methods: The aim of this study is to identify whether the assessment Non-Small Cell Lung Cancer (NSCLC) patients report when answering the BFI questionnaire of fatigue is consistent with the one recorded by the clinical team at the pneumology consultation the during treatment with immunotherapy in monotherapy or in combination with chemotherapy. A prospective observational study was carried out during 8 months. The research was conducted through the collection of medical records from the patients clinical files and the application of the Brief Fatigue Inventory questionnaire before each one of the 4 treatment cycles. This questionnaire was validated and linguistically translated into Portuguese and assesses the severity and functional impact of fatigue in cancer patients. A 95% confidence interval was considered. Results: The 31 patients, 26 male (84%) and 5 female (16%) with a mean age of 68.5 years. The mean value of the BFI score before the first treatment, as well as in the following 3 evaluations, was higher for the participants who presented symptoms of asthenia/tiredness/fatigue recorded in the clinical files at the consultation and lower for those who did not. However, the differences were not statistically significant (pre 1st treatment - p=0.299, pre 2nd treatment - p=0.125, pre 3rd treatment - p=0.103 and pre 4th treatment - p=0.954). By comparing the BFI score with medical records, we found that fatigue remained underreported at the consultation in different assessment times (71% of sample participants were not identified as having fatigue at the 1st assessment time; 60% at the pre 2nd treatment visit; 54% at the pre 3rd treatment visit and 40% at the pre 4th treatment visit). Conclusions: In the present study, the BFI questionnaire allowed us to identify and stratify fatigue, showing greater sensitivity when compared to the medical records of the consultation alone.
Innovative platforms for development of TCR-T cell therapies against novel tumor targets: Triple negative breast cancer.
Authors: Rachel Judith Mary Abbott, Dora Hammerl, Dian Kortleve, Mandy van Brakel, Rebecca Wijers, Daphne Roelofs, Madelon Badoux, Reno Debets
Journal: Journal of Clinical Oncology (2023)

e14536 Background: Adoptive T cells therapies have shown great potential over the past decade, particularly with the use of CAR-T cells to treat haematological tumors. However, their effect in the treatment of solid cancers is limited, due to a lack of relevant therapeutic targets and suppressive mechanisms of the tumor microenvironment. To counteract these challenges, we have developed Pan Cancer T (PCT) platforms to yield novel TCR-T cell therapies against untapped (intracellular) tumor targets exclusively expressed in 10 hard-to-treat solid tumors (including breast, melanoma, colorectal, glioma, lung cancer). Furthermore, we are developing engineering strategies aiming to improve the longevity of T cells within the inhibitory solid tumor microenvironment. Methods: The platforms we have developed to enable generation of genetically engineered TCR-T cells to recognize tumor-specific (intracellular) antigens include: 1) PCT Target Discovery (identifying and selecting safe, immunogenic tumor targets by combining advanced in silico and laboratory techniques); 2) PCT TCR Discovery (identifying, selecting, and validating potent TCR-T cells binding with high specificity and avidity); 3) PCT Next Gen Engineering (identifying drivers of immune evasion and implementing TCR-T cell-based gene-engineering approaches to overcome suppression and/or improve durability). Results: Using our PCT Target Discovery platform, we have validated a set of 30 unique tumor targets which are safe, immunogenic and highly shared. Our first showcase target is PCT-1, which is of particular interest in triple negative breast cancer (TNBC), where it is expressed by &gt;85% of patients, with high homogeneity in &gt;80% of all tumor cells. PCT-1 is also expressed in other tumor types, including &gt;90% melanoma and &gt;45% multiple myeloma patients. The PCT TCR Discovery platform has enabled development of a highly specific and active TCR against PCT-1, which outperformed standard of care TNBC treatments (ie, cis-platinum and sacituzumab govitecan) in advanced preclinical efficacy models, including in vitro killing of patient-derived 3D organoids and an in vivo model in NSG mice. Conclusions: The PCT platforms have enabled development of a promising TCR-T against a novel target antigen expressed in TNBC, an aggressive form of breast cancer that affects younger women with limited treatment options. A portfolio of 29 additional untapped targets has also been identified, providing potential to generate TCR-based therapies for treatment against a much larger range of solid tumors. Furthermore, we are developing next generation technologies, aiming to enhance the durability of responses within the hostile tumor microenvironment, which should be broadly applicable to TCR-T therapies.
Safety and feasibility of JAK inhibitor ruxolitinib in newly-diagnosed high-grade gliomas (CRUX): Final toxicity report.
Authors: Manmeet Singh Ahluwalia, Ahmad Ozair, Atulya Aman Khosla, Yasmeen Rauf, Wei Wei, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, Glen Stevens, David M. Peereboom
Journal: Journal of Clinical Oncology (2023)

2060 Background: Dysregulation of the JAK/STAT pathway in newly-diagnosed high-grade gliomas (nHGG) is linked to enhanced survival and proliferation of tumor cells. Ruxolitinib, a small molecule inhibitor of JAK1, JAK2, and JAK3, limits glioma growth in preclinical models. This concept was explored in a phase I trial (NCT03514069), whose final report on toxicity is presented here. Methods: This non-randomized prospective study included 60 WHO Grade 3-4 nHGG patients who received standard of care (SOC) therapy along with ruxolitinib in a 3+3 dose-escalation design; level 1 of 10 mg BID, level 2 of 15 mg BID, level 3 of 20 mg BID, level -1 of 5 mg BID. The primary study objective was the determination of the maximum tolerated dose (MTD) of ruxolitinib in combination with chemoradiation. The secondary objective was the determination of safety, overall survival (OS), and progression-free survival (PFS). The exploratory aims were to investigate relationships between clinical outcomes and genomic signatures. Results: 60 patients were enrolled, with a median age of 60.5 years (range 22-78). 23 (38%) patients were female and 37 (62%) were male. 29 (48%) were MGMT unmethylated and received ruxolitinib with radiation of 60 Gy over 6 weeks. 31 (52%) patients were MGMT methylated and received ruxolitinib with 75 mg/m 2 of temozolomide (TMZ) with radiation of 60 Gy over 6 weeks. The 1-year OS rate was 77% for all GBM patients; 62% for arm 1 (unmethylated MGMT) and 93% for arm 2 (methylated MGMT). Median OS for arm 1 was 18.1 months (10.1, NA) and was not reached for arm 2. MTD for both cohorts was 20 mg BID. No dose-limiting toxicities were observed. Toxicities attributable to study medications included four grade 4 AEs including seizure, respiratory distress, somnolence, and thromboembolic event along with 14 grade 3 adverse events (AEs), including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and meningitis. Conclusions: Ruxolitinib therapy is safe and feasible in combination with TMZ and radiation. Efficacy of ruxolitinib plus SOC appears promising compared to historical benchmarks for both MGMT methylated and MGMT unmethylated cohorts. A randomized phase 2 trial is planned. Clinical trial information: NCT03514069 .
The role of micro-CT for intraoperative margin assessment of breast cancer.
Authors: Mahtab Vasigh, Seyed Mostafa Meshkati Yazd, Andreas S. Papazoglou, Alexandros Liatsos, Keivan Ranjbar, Richard J. Bleicher, Austin David Williams, Christian X. Cruz Pico, Matthew Lewis Pierotti, James Michaelson
Journal: Journal of Clinical Oncology (2023)

e13620 Background: Breast-conserving surgery (BCS) followed by radiotherapy requires adequate removal of the malignancy with a negative margin. Accurate pathologic margin status is not available intraoperatively and is found to be positive in up to 20% of cases, necessitating re-excision. Specimen mammography (SM), used to find a biopsy marker, may assist with margin status but is only 55% sensitive for Intraoperative margin assessment (IMA). IMA methods are being increasingly investigated. Because micro-computed tomography (micro-CT) produces three-dimensional volumetric images, we aimed to evaluate the diagnostic sensitivity of micro-CT for IMA. Methods: We performed a systematic review according to the PRISMA guidelines by querying Scopus, MEDLINE, EMBASE, PubMed, and Google Scholar through 12/21/22. (https://osf.io/342h8). Studies evaluating the applications of micro-CT scanning in breast cancer were included for systematic review, and those reporting the diagnostic indices of micro-CT for IMA compared to histopathologic results were incorporated in a study-level meta-analysis. A random effects coefficient binary regression model was used when a high level of heterogeneity was observed. Results: Of the 2920 studies, 18 studies were selected. IMA was reported in 7 studies (388 specimens), tumor size in 3 studies, microcalcifications in 12 studies, and sentinel lymph node assessment in 1 study. Half of the studies were performed in the USA; the participant’s ages ranged from 33 to 82 years, and the tumor size was between 0.8 and 55.8mm. Image procurement time ranged from 4 to 30 minutes. A pooled diagnostic sensitivity of 0.67 (95% CI: 0.48 – 0.82) and specificity of 0.75 (95% CI: 0.63 – 0.84) was revealed, and the pooled accuracy was calculated based on the normal-error estimation as 0.76 (95% CI: 0.69 – 0.83) for IMA by micro-CT compared to the histopathological evaluation. Conclusions: Micro-CT can create 3D images of the internal structure and vasculature in less than 30 minutes and detects up to 67% of positive margins intraoperatively, preventing a future reoperation. Although the results of this review are promising, due to the high level of heterogeneity, further investigations should be pursued as to how and who should report the images and whether micro-CT may have a role in IMA. [Table: see text]
Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results.
Authors: Benedito A. Carneiro, Ruth Perets, Afshin Dowlati, Patricia LoRusso, Kan Yonemori, Lei He, Wijith Munasinghe, Behnam Noorani, Eric Feral Johnson, Jon Zugazagoitia
Journal: Journal of Clinical Oncology (2023)

3027 Background: Mirzotamab clezutoclax (ABBV-155; Mirzo-C) is a first-in-class antibody-drug conjugate with three components: an anti–B7-H3 monoclonal antibody, a solubilizing linker, and a BCL-X L inhibitor payload. By specific targeting of BCL-X L , synergy with other anticancer agents was observed in preclinical models. When combined with a taxane, clinical antitumor activity was reported in relapsed and/or refractory (R/R) solid tumors during the dose escalation phase of an ongoing Phase 1, open-label study (NCT03595059). Methods: In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C was administered at the recommended Phase 2 dose determined at dose escalation. Primary objectives were safety and overall response rate (ORR). Results: As of November 18, 2022, 78 patients were enrolled (SCLC n=14; NSCLC n=36; BrCa n=28). The median (range) follow-up was 2.0 (0.6–9.1) months for the SCLC cohort, 4.9 (0.6–8.5) for NSCLC, and 10.4 (0.8–13.3) for BrCa. The median number of prior lines of systemic therapy was 2 in the SCLC cohort, 2 in NSCLC, and 6 in BrCa. Prior taxane therapy was received by 7% of patients in the SCLC cohort, 36% in NSCLC, and 64% in BrCa. The most common adverse events (AEs) in SCLC were fatigue, increased aspartate aminotransferase, diarrhea, and headache (21%, n=3 for each AE); fatigue was the most common AE in NSCLC (58%, n=21; Grade 3/4: 3%, n=1) and in BrCa (61%, n=17). Thrombocytopenia, a result of the systemic effects of BCL-X L inhibitors, was not observed in the Mirzo-C monotherapy cohort. Neutropenia/decreased neutrophil count was not observed in the SCLC monotherapy cohort but was common with BrCa paclitaxel combo (64%, n=18; Grade 3/4: 29%, n=8) and NSCLC docetaxel combo (53%, n=19; Grade 3/4: 44%, n=16); 5 patients in the NSCLC cohort (14%) and 1 in BrCa (4%) had febrile neutropenia. Confirmed ORR was 0% in the SCLC cohort, 11% in NSCLC, and 18% in BrCa. Conclusions: Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC. Combination treatments were active with high best overall response (BOR) and disease control rates in heavily pretreated NSCLC and BrCa patients, where Grade 3/4 neutropenia was observed. It is unknown if Mirzo-C exacerbated the neutropenia risk associated with taxanes. Clinical trial information: NCT03595059 . [Table: see text]
"Armed" CEA CAR-T with a SIRPγ-CD28 chimeric co-receptor to exhibit the enhanced antitumor activity in preclinical study of colorectal cancer.
Authors: Yongchun Zhao, Xiuxiu Zhu, Junjie Shen, Yanmin Xu, Zhi Yang, Yanan Qi, Jun Chen, Juan Hong, Linling Wang, Lei Qin, Ge Liu, Xia Huang, Jingwen Hu, Wenxu Zhao, Yunfan Chen, Xiaorui Jiang, Liurong Jiao, Nan Chen, Cheng Qian
Journal: Journal of Clinical Oncology (2023)

e14530 Background: Nowadays, CAR-T cell therapy still faces limited therapeutic efficacy for solid tumors. SIRPγ is known as a ligand for a well-known immune checkpoint molecule CD47. It is distinguished from other members of its family in that it has a very short intracytoplasmic tail and is incapable of transducing signals on its own. Of note, the role of SIRPγ still largely unknown to date. Preliminary data indicated SIRPγ plays a key role in T-cell transendothelial migration and promotes antigen-specific T-cell proliferation. We thus designed a novel SIRPγ-CD28 chimeric receptor comprising the extracellular part of SIRPγ, the transmembrane and intracellular domains of CD28 and used as the co-receptor for a CEA-targeting CAR. Here, we report on the activity of this "armed" CAR-T with the SIRPγ-CD28 co-receptor in colorectal tumor (CRC) and its anti-tumor efficacy in mice xenograft model. Methods: In vitro luciferase-based cytotoxicity assay were used by coculturing CAR-T and DLD1-CEA CRC cells to assess the activities of CAR-T w/wo the co-receptor. The incubation supernatants were collected for detecting the release of cytokines. In vivo evaluation of the anti-tumor efficacy of CAR-T with the SIRPγ-CD28 co-receptor versus control T cell, and control CAR-T was performed in NOG mice CRC xenograft model. DLD1-CEA cells expressing luciferase reporter were s.c. implanted and T cells were i.v. injected. Anti-tumor efficacy was assessed by in vivo system. Results: CAR-T with the SIRPγ-CD28 co-receptor exhibited specific cytotoxicity only to CEA + CRC cells, and the efficacies of CAR-T w/wo the co-receptor were comparable (88.6% vs 87.8%, p &gt; 0.05). However, cytokines were significantly higher in the CAR-T group with the co-receptor. The levels of IFNγ, IL2 and TNFα in groups of CAR-T w/wo the co-receptor were 72,793.33 vs 19,013.33 pg/ml (p &lt; 0.05), 1834.67 vs 25.15 pg/ml (p &lt; 0.05) and 79.65 vs 0 pg/ml (p &lt; 0.05), respectively. In mice CRC xenografts model, the tumors were totally eliminated in the CAR-T group with the co-receptor at 21 days and lasted until the end of experiment, while the tumor growth was suppressed in the control CAR-T group at first and out-of-control in the end (Table). Conclusions: These preclinical studies demonstrated the potential of SIRPγ-CD28 co-receptor as a novel T cellular activation signals for CAR-T. The "armed" CAR-T exhibits a fabulous anti-tumor efficacy in CRC and has great potential for applications in other solid tumors. [Table: see text]
Extracellular vesicles budding from stromal macrophages from the blood circulating in patients with metastatic non-small cell lung cancer to predict clinical outcomes.
Authors: Jillian Moran, Daniel L Adams, Martin Joseph Edelman, Pablo Lopez Bravo, Ting Xu, Zhongxing X. Liao, Kirby P Gardner, Cha-Mei Tang, Steven H. Lin
Journal: Journal of Clinical Oncology (2023)

e14547 Background: Extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies, are involved in cellular communication, aiding tumor growth, and in metastasis of cancer. Recently, extracellular budding structures on Cancer Associated Macrophage-Like Cells (CAMLs), a subtype of phagocytic circulating stromal cells found in circulation, was observed in patients with metastatic non-small cell lung carcinoma (mNSCLC). In this prospective analysis of n=104 metastatic NSCLC (mNSCLC) patients, we enumerated EV budding on CAMLs to determine their clinical significance on Progression Free Survival (PFS) &amp; Overall Survival (OS), further subtyping based on treatment with or without PD-L1 Immunotherapy (IMT) based on standard of care treatment. These preliminary data suggests that EV positive (EV+) CAMLs prognosticates for worse PFS &amp; OS in mNSCLC. Methods: We initiated a single blind multi-year prospective study to investigate the relationship between EV budding in CAMLs to PFS &amp; OS prior to start of new treatment lines for mNSCLC. Anonymized blood was procured from n=104 pathologically confirmed mNSCLC patients and filtered to isolate CAMLs to measure EV budding using tumor/EV markers (i.e. cytokeratin, CD63, or CD81) and an immune specific marker (PD-L1). Blood was filtered by CellSieve microfiltration and EV budding was characterized as small (≤1 µm) bulbous protrusions from the cell cytoplasm. EVs were quantified by presence (EV+) or absence (EV-), as well asPD-L1 positivity or negativity in EVs, to compare PFS &amp; OS with hazard ratios (HRs) at 60 months by censored univariate and multivariate analyses. Results: CAMLs were identified in 93% (n=97/104) of all samples, with EV budding (EV+) identified in 62% (n=60/97) of CAMLs. At 60 month follow-up, it was determined that EV+ CAMLs was associated with significantly worse PFS (HR=1.67 95%CI=0.4-1.0, p=0.0410) and OS (HR=1.88, 95%CI=0.3-0.9, p=0.0108). Further, in patients not treated with IMT, EV+ CAMLs was associated with significantly worse PFS (HR=2.51, 95%CI=0.2-0.8, p=0.0251) and OS (HR=2.32, 95%CI=0.2-0.9, 0.0407). In contrast, in patients treated with IMT, EV+ CAMLs had no correlation to PFS (1.18, 95%CI=0.5-1.6, p=0.7050) or OS (HR=1.53, 95%CI=0.3-1.3, p=0.2858), suggesting a clinical benefit in treating EV+ patients with PD-L1 IMT. Conclusions: EV budding on phagocytic stromal cells found in the blood of mNSCLC patients appears to predict for poorer PFS and OS, which is reduced with additional of PD-L1 immunotherapies. Larger validation studies are ongoing in both mNSCLC and stage III NSCLC patients, along with analysis of PD-L1 EV staining.